Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
  • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
  • C07K1/1075—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of amino acids or peptide residues
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to a novel guanidine derivative and others.
• a guanidino group is known to form a hydrogen bond with, for example, a sulfate group, a carboxy group, or a phosphate group by electrostatic interactions.
• Arginine is known as a natural amino acid having a guanidino group, and the guanidino group of arginine is known to play an important role in interaction with cell membranes, cell entry, or the like in a living body.
• arginine is a natural amino acid, it is prone to be degraded by a protease or the like. Therefore, if arginine is to be used as a medicament, issues concerning blood half-life or the like are apt to occur.
• F4G 4-Guanidinophenylalanine
• arginine J. Med. Chem 2012, 55, 10287-10291.
• This compound is resistant to trypsin (Chem. Pharm. Bull. 1986, 34(3), 1351-1354), and has a high stability (J. Med. Chem. 2012, 55, 6294-6305), and thus is one of the amino acid derivatives that are emphasized in peptide pharmaceuticals.
• a method for synthesis of F4G a method using mercury or silver is known (Tetrahedron Letters 1996, 37, 48, 8711-8714).
• the method uses heavy metals, it is costly to produce F4G, and waste solvents are problematic.
• An object of the present invention is to provide a guanidine derivative (in particular, an amino acid compound having a 4-guanidino group) that is produced at a low cost and with a low probability of occurrence of waste solvent problems, a method for manufacture of the derivative, and an intermediate used for the manufacture of the derivative.
• a guanidine derivative in particular, an amino acid compound having a 4-guanidino group
• a first aspect relates to a compound represented by the following Formula (I) (a novel guanidine compound), a tautomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
• a second aspect relates to a method for manufacture of a peptide using the above-described compound, a tautomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
• a third aspect relates to a method for manufacture of a compound represented by Formula (I), a tautomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, the method including a mixing step in which a compound represented by the following Formula (II) is mixed with a compound represented by the following Formula (III).
• a guanidine derivative in particular, an amino acid compound having a 4-guanidino group
• a guanidine derivative can be obtained at a low cost and with a low probability of occurrence of waste fluid problems.
• a novel guanidine derivative of the present invention relates to a compound represented by the following Formula (I), a tautomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
• the group A consists of a halogen atom, an amino group, a nitro group, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkylthio group, and a C 1-3 halogenoalkyl group.
• R 11 — represents a C 6-10 arylene group which may have one or more substituent groups selected from the group A.
• R 12 — represents a C 1 -C 4 alkylene group which may have one or more substituent groups selected from the group A.
• R 2 and R 4 may be the same or different and represent a protecting group or a hydrogen atom, and R 3 represents a hydrogen atom.
• R 5 represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a nitro group, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkylthio group, or a C 1-3 halogenoalkyl group.
• R 5 may be taken together with —N—R 1 — to form a C 5-7 heterocyclic amine which may have an asymmetric carbon atom at the alpha-position.
• R 6 and R 7 may be the same or different and represent a protecting group, a C 1-5 alkyl group or a hydrogen atom.
• R 8 represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a nitro group, a C 1-5 alkyl group, a C 1-3 alkoxy group, a C 1-3 alkylthio group, a C 1-3 halogenoalkyl group or a group represented by —O—R 13 —.
• R 8 may be a protecting group of an amino acid.
• the group represented by R 13 — represents a protecting group of an oxygen atom, a C 1-5 alkyl group, a C 1 -3 alkoxy group, a C 1 -3 alkylthio group, or a C 1-3 halogenoalkyl group.
• the tautomers thereof refer to tautomers of a compound represented by Formula (I).
• the tautomers refer to isomers in which the isomers are rapidly converted to each other, i.e., isomerized, and an equilibrium state in which both of the isomers coexist can be achieved.
• the enantiomers thereof refer to enantiomers of a compound represented by Formula (I).
• the enantiomers refer to isomers in which one of the two molecules is a chiral molecule (a mirror image) of the other, and the molecule cannot be superposed on the other and vice versa.
• the pharmaceutically acceptable salt thereof refers to a pharmaceutically acceptable salt of a compound represented by Formula (I).
• the pharmacologically acceptable salt include salts formed with an inorganic base, ammonia, an organic base, an inorganic acid, an organic acid, a basic amino acid, a halogen ion, and the like, and an inner salt.
• the inorganic base include an alkali metal (Na, K, etc) and an alkaline earth metal (Ca, Mg, etc).
• Examples of the organic base include trimethylamine, triethylamine, choline, procaine, ethanolamine, dicyclohexyl amine, cyclohexyl amine, cinchonidine, pyridine, lutidine, triethylenediamine, and the like.
• Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and the like.
• Examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, and maleic acid, and the like.
• Examples of the basic amino acid include lysine, arginine, ornithine, histidine, and the like.
• the pharmaceutically acceptable solvate thereof refers to a pharmaceutically acceptable solvate of a compound represented by Formula (I).
• An example of the solvate is a hydrate.
• a compound of the present invention sometimes absorbs moisture present in the air during storage, and forms a hydrate.
• the present invention embraces such a hydrate.
• the pharmaceutically acceptable solvate thereof may be a solvate of a pharmaceutically acceptable salt of a compound represented by Formula (I).
• Preferred examples of the compound represented by Formula (I) are those in which —R 1 — represents a group represented by —R 11 —R 12 —.
• —R 11 — represents a 1,3-phenylene group or a 1,4-phenylene group which may have one or more substituent groups selected from the group A, and the group represented by —R 12 — represents a C 1-4 alkylene group.
• more preferred are those in which —R 11 — represents a 1,3-phenylene group or a 1,4-phenylene group, and the group represented by —R 12 — represents a C 1-4 alkylene group.
• R 5 , R 6 , R 7 , and R 8 represent the following groups are preferred.
• R 5 represents a hydrogen atom, a methyl group, or an ethyl group.
• R 6 represents an Fmoc group (9-fluorenylmethyloxycarbonyl group).
• R 7 represents a hydrogen atom.
• R 8 represents a hydroxy group, or a group represented by —O—R 13 —, wherein
• Preferred examples of the compound represented by Formula (I) other than those described above are those in which —R 1 — represents a C 3 -C 6 alkylene group. Among these, those in which —R 1 — represents a C 4 alkylene group are preferred examples.
• Preferred examples of the compound represented by Formula (I) are those in which —R 1 — represents a C 4 alkylene group, R 2 represents a protecting group (e.g., Rbf-), R 3 represents a hydrogen atom, R 4 represents a protecting group (e.g., Sub-), R 5 represents a methyl group, R 6 represents an Fmoc group, R 7 represents a hydrogen atom, R 8 represents a hydroxy group (e.g., N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(N-((10,11-dihydro-5H-dibenzo[a,d][7]annulene-5-yl)-N-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)carbamimidoyl)-N6-methyl-L-lysine).
• R 2 represents a protecting group (e.
• R 1 — in Formula (I) represents a C 3 -C 6 alkylene group
• R 5 , R 6 , R 7 , and R 8 represent the following groups are preferred.
• R 5 represents a hydrogen atom, a methyl group, or an ethyl group.
• R 6 represents an Fmoc group (9-fluorenylmethyloxycarbonyl group).
• R 7 represents a hydrogen atom, a methyl group, or an ethyl group.
• R 8 represents a hydroxy group, or a group represented by —O—R 13 —, wherein
• R 7 is a hydrogen atom
• R 8 is a protecting group (a protecting group of an amino acid), a C 1-5 alkyl group or a hydrogen atom (i.e., a compound being a peptoid and having a piperazine ring).
• C m-n means that the number of carbon atoms is any one of from m to n.
• An alkyl group refers to a monovalent group which is formed by removing one hydrogen atom from a linear or branched aliphatic hydrocarbon.
• Examples of a C 1-5 alkyl group are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an iso-pentyl group, and a neopentyl group.
• Examples of a C 1 -C 4 alkyl group are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.
• An alkoxy group refers to a monovalent group which is formed by removing a hydrogen atom from a hydroxyl group of a linear or branched alcohol.
• Examples of a C 1-3 alkoxy group are a methoxy group, an ethoxy group, a propoxy group, and an iso-propoxy group.
• An alkylthio group refers to a group in which an oxygen atom of an alkoxy group is substituted by a sulfur atom.
• Examples of a C 1-3 alkylthio group are a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group.
• a halogenoalkyl group refers to a monovalent group in which one or more hydrogen atoms of an alkyl group are substituted by one or more halogen atoms.
• Examples of a C 1-3 halogenoalkyl group are a trifluoromethyl group, a trichloromethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a fluoromethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a 2-bromoethyl group, a 2-chloroethyl group, a 2-fluoroethyl group, a 2-iodoethyl group, a 3-chloropropyl group, and a 4-fluorobutyl group.
• An alkylene group refers to a divalent group which is formed by removing two hydrogen atoms from a linear or branched aliphatic hydrocarbon.
• Examples of a C 1-10 alkylene group are a methylene group, a methylmethylene group, an ethylene group, a propylene group, a trimethylene group, a 1-methylethylene group, a tetramethylene group, a 1-methyltrimethylene group, a 2-methyltrimethylene group, a 3-methyltrimethylene group, a 1-methylpropylene group, a 1,1-dimethylethylene group, a pentamethylene group, a 1-methyltetramethylene group, a 2-methyltetramethylene group, a 3-methyltetramethylene group, a 4-methyltetramethylene group, a 1,1-dimethyltrimethylene group, a 2,2-dimethyltrimethylene group, a 3,3-dimethyltrimethylene group, a hexamethylene group, a 1-methylp
• An arylene group refers to a divalent group which is formed from an aromatic hydrocarbon by removing two hydrogen atoms bonded to the ring.
• Examples of the ring that constitutes a C 6-10 arylene group are a benzene ring or a naphthalene ring.
• halogen atoms are fluorine, chlorine, bromine, and iodine.
• Examples of the protecting group are 10,11-dihydro-5H-dibenzo-[a,d][7]annulene-5-yl group (Sub), a diphenylmethyl group (Bzh), a 4-methoxyphenylmethyl group (PMB), a tert-butyl group (tBu), a tert-butoxycarbonyl group (Boc), a 9-fluorenylmethyloxycarbonyl group (Fmoc), a tosyl group (Tos), a nitro group (NO 2 ), a 4-methoxy-2,3,6-trimethylbenzenesulfonyl group (Mtr), a 2,2,5,7,8-pentamethylchroman-6-sulfonyl group (Pmc), a 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl group (Pbf), benzyloxycarbonyl group (Z), a 2-ch
• the guanidine derivative of the present invention has a guanidino group, and thus peptides and proteins can be synthesized by joining the guanidino group. Furthermore, the above-described compound and the like and an amino acid can be mixed together and reacted to obtain a peptide.
• the novel thiourea compound as an intermediate used for manufacture of the guanidine derivative is a compound represented by the following Formula (II).
• R 22 and R 24 may be the same or different and represent a protecting group or a hydrogen atom.
• the protecting group are Pbf, Pmc or Sub. Among these, preferred are those in which R 22 and R 24 are Pbf and Sub, respectively.
• R 23 represents a hydrogen atom.
• novel thiourea compounds of the present invention can be manufactured according to the following scheme.
• R 2 and R 4 may be the same or different and represent a protecting group or a hydrogen atom. Indeed, in Formula 1-1, Formula 1-3, Formula 1-4, those in which R 2 and R 4 each represent a protecting group are preferred. Examples of R 2 and R 4 are Pbf and Sub, respectively.
• R 3 represents a hydrogen atom.
• X 1-1 represents an alkali metal (e.g., Na, K) or an alkaline earth metal (the compositional formula of X 1-1 SCN varies depending on the valency of a cation).
• a compound represented by Formula 1-1 is dissolved in an organic solvent (e.g., N,N-dimethylformamide: DMF). To this solution is added a compound represented by Formula 1-2, and the solution is stirred to obtain a solution containing a compound represented by Formula 1-3.
• the molar ratio of compounds represented by formula 1-1 and formula 1-2 may be 1:2 to 2:1, 2:3 to 3:2, or 4:5 to 5:4.
• the reaction temperature may be 10° C. or higher and 60° C. or lower, or 20° C. or higher and 40° C. or lower.
• the reaction time may be 10 minutes or more and 3 hours or less, or 20 minutes or more and 1 hour or less.
• a known catalyst may be added to the reaction system. The stirring speed may be properly adjusted.
• a compound represented by Formula 1-4 is dissolved in an organic solvent (e.g., DMF). To this solution is added a strong base (e.g., NaH) with cooling. The resulting solution with the added strong base is stirred to obtain a reaction solution (e.g., suspension).
• an organic solvent e.g., DMF
• a strong base e.g., NaH
• the resulting solution with the added strong base is stirred to obtain a reaction solution (e.g., suspension).
• the molar ratio of compounds represented by Formula 1-1 and Formula 1-4 may be 1:2 to 2:1, 2:3 to 3:2, or 4:5 to 5:4.
• the temperature when a strong base is added to the compound represented by Formula 1-4 is ⁇ 20° C. or higher and 10° C. or lower, and may be ⁇ 10° C. or higher and 5° C. or lower.
• the temperature of the solution while stirring may be 10° C. or higher and 60° C. or lower, or 20° C. or higher and 40° C. or lower.
• the reaction time may be 5 minutes or more and 2 hours or less, or 10 minutes or more and 1 hour or less.
• a known catalyst may be added to the reaction system. The stirring speed may be properly adjusted. Consequently, a solution containing a compound represented by Formula 1-4 is obtained.
• a solution containing a compound represented by Formula 1-3 is added to the solution containing a compound represented by Formula 1-4, and the resulting solution is stirred to promote a reaction and obtain a solution containing a compound represented by Formula 1-5.
• the temperature of the solution while stirring may be 10° C. or higher and 60° C. or lower, or 20° C. or higher and 40° C. or lower.
• the reaction time may be 10 minutes or more and 4 hours or less, or 30 minutes or more and 2 hours or less.
• reaction solution can be purified and dried using known methods for purification and/or drying to obtain a compound represented by Formula 1-5.
• a strong acid e.g., hydrochloric acid
• the guanidine derivative of the present invention can be manufactured according to the following scheme. This step utilizes a reaction in which when the C-terminal of an amino acid of a side chain is not protected, a protecting group derived from a silylation reagent protects the unprotected C-terminal of the amino acid of the side chain.
• R 1 to R 8 have the same meaning as provided above.
• a compound represented by Formula 2-2 is mixed with an organic solvent (e.g., tetrahydrofuran: THF), and in particular when the C-terminal is not protected (i.e., when R 8 is a hydroxy group), a silylation reagent (e.g., MSA) is added and the resulting mixture is stirred.
• an organic solvent e.g., tetrahydrofuran: THF
• a silylation reagent e.g., MSA
• the molar ratio of the compound represented by Formula 2-2 and the silylation reagent may be 1:4 to 2:1, 1:3 to 1:1, or 1:2 to 1:1.
• the temperature of the solvent while stirring may be 10° C. or higher and 90° C. or lower, or 20° C. or higher and 80° C. or lower.
• the stirring time may be 20 minutes or more and 3 hours or less, or 30 minutes or more and 2 hours or less.
• a liquid containing the above-described compound represented by Formula 2-2 are added a compound represented by Formula 1-5 and a condensing agent, and the resulting mixture is stirred.
• An organic base e.g., TEA
• the condensing agent may be a known condensing agent, and an example is dimethylaminopropylethylcarbodiimide hydrochloride (EDCI).
• EDCI dimethylaminopropylethylcarbodiimide hydrochloride
• the stirring time may be 10 minutes or more and 2 hours or less, or 20 minutes or more and 1 hour or less.
• an acid e.g., citric acid
• the molar ratio of compounds represented by Formula 2-1 and Formula 1-5 may be 1:2 to 2:1, 2:3 to 3:2, or 4:5 to 5:4.
• a liquid containing a compound represented by formula 2-3 can be obtained.
• a compound represented by formula 2-3 can be obtained by extraction, purification, and/or drying. Note that the extraction may include treatments such as salt formation or purification.
• the group R 2 or R 4 in the compound represented by 2-3 is a protecting group
• the group can be deprotected to obtain a deprotected guanidine derivative of the present invention.
• a guanidine derivative of the present invention can be used for the following applications.
• a guanidine derivative (in particular, a salt) of the present invention easily forms a hydrogen bond, and thus utilized as a denaturant of a protein.
• a guanidine derivative of the present invention is utilised as a strong base in organic synthesis.
• a guanidine derivative of the present invention has a guanidino group, and thus peptides and proteins can be synthesized by joining the guanidino group.
• a guanidine derivative or a peptide of the present invention has a cell membrane-permeating property, and thus also has efficacy as a carrier of a drug delivery system.
• High performance liquid chromatography/mass spectrometry was measured, unless otherwise specified, by any of ACQUITY UPLC H-Class/QDa (manufactured by Waters Corporation), ACQUITY UPLC H-Class/SQD2 (manufactured by Waters Corporation), or LC-20AD/Triple Tof5600 (manufactured by SHIMADZU CORPORATION).
• ESI+ refers to positive mode in electrospray ionization
• M+H refers to a proton adduct
• M+Na refers to a sodium adduct.
• ESI ⁇ refers to a negative mode in electrospray ionization
• M ⁇ H refers to a proton lost form
• the ratio between a raw material and a product was calculated from the area ratio of peaks obtained under the following analysis conditions in high performance liquid chromatography/mass spectrometry, and the structure of the resulting compound was confirmed by 1H-NMR and LC/MS.
• the reaction mixture was cooled to 0° C., thereafter the reaction was quenched with 1 M hydrochloric acid aqueous solution (110 mL), and the reaction mixture was added to 1000 mL of water.
• the resulting solid was filtered, and the solid was dried at 60° C. under reduced pressure overnight.
• the resulting solid was suspended in ethyl acetate/heptane (1/2, 300 mL), and then the solid was filtered, dried under reduced pressure to obtain the titled compound (42.5 g, 82 mmol, 82% yield).
• the structure was confirmed by 1H-NMR and LC/MS.
• the reaction solution was diluted with 15 mL of ethyl acetate, the reaction was quenched with 1 M sulfuric acid aqueous solution, and then the mixture solution was extracted with ethyl acetate. The resulting organic layer was washed four times with water, then dried with sodium sulfate, and thereafter filtered and concentrated under reduced pressure. The resulting residue was dissolved in DCM (5 mL), and heptane (30 mL) was added to the solution and stirred for 18 hours. The resulting pale-yellow solids were filtered, and the solids were washed with heptane to obtain the titled compound. The structure was confirmed by 1H-NMR and LC/MS.
• the titled compound was obtained by the same method as in Example 2, except that N-Fmoc-4-amino-L-phenylalaninemethyl; methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-aminophenyl)propanoate was used and the MSA treatment was omitted.
• the titled compound was obtained by synthesis and purification according to known methods. The product was confirmed by 1H-NMR.
• the resulting compound was deprotected by the same method as in (1).
• the deprotection treatment was performed for 60 min, and then production of Fmoc-F4G-OH; (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-guanidinophenyl)propanoic acid was confirmed by LC/MS (Analysis condition A).
• the titled compound was obtained by synthesis and purification according to known methods. The product was confirmed by 1H-NMR.
• the resulting compound was deprotected by the same method as in (1).
• the deprotection treatment was performed for 60 min, and then production of Fmoc-F4G-Met; methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-guanidinophenyl)propanoate was confirmed by LC/MS (Analysis condition A).
• the titled compound was obtained by synthesis and purification according to known methods. The product was confirmed by 1H-NMR. The resulting compound was deprotected by the same method as in (1). The deprotection treatment was performed for 60 min, and then the production of Fmoc-F4G-Met; methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-guanidinophenyl)propanoate was confirmed by LC/MS (Analysis condition A).
• the reaction was quenched with 0.5 N citric acid aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, and then dried with sodium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and hexane in a volume 9 times the volume of the solution was added to the solution and stirred overnight. The resulting precipitate was filtered, and the precipitate was dried to obtain the titled compound (2.1 g, 2.362 mmol, 95% yield) as pale-yellow solids. The structure was confirmed by 1H-NMR and LC/MS.
• N-Fmoc-L-lysine hydrochloride (1.00 g, 2.47 mmol) was suspended, then MSA (0.99 mL, 6.17 mmol) was added, and the mixture was stirred at room temperature for 30 min.
• N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-aminopropyl)glycine hydrochloride (3.91 g, 10.0 mmol).
• To the flask were added 95 mL of THF and MSA (3.82 mL, 23.81 mmol) under room temperature, and the mixture was stirred at room temperature for 30 min.
• the reaction was quenched with a saturated citric acid aqueous solution at room temperature, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and saturated sodium chloride solution, then dried with sodium sulfate, and then filtered and concentrated under reduced pressure. The resulting residue was suspended and washed with hexane/ethyl acetate (60 mL/30 mL), to obtain the titled compound (8.28 g, 9.84 mmol, 103% yield). The structure was confirmed by 1H-NMR and LC/MS.
• the reaction solution was stirred for 30 min in the water bath, then the reaction was quenched with 10% citric acid aqueous solution, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed twice with water, and once with 10% sodium chloride solution, then dried with sodium sulfate, and then filtered and concentrated under reduced pressure. To the resulting residue was added 300 mL of hexane, the mixture was stirred at 50° C. for 1 hour, and then gradually cooled to room temperature with stirring. The resulting pale-yellow solids were filtered, and the solids were washed with hexane to obtain the titled compound (35.1 g, 36.7 mmol, 98% yield). The structure was confirmed by 1H-NMR and LC/MS.
• the reaction solution was stirred at room temperature for 30 min, then the reaction was quenched with 10% citric acid aqueous solution, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed twice with water, and once with saturated sodium chloride solution, then dried with sodium sulfate, and then filtered and concentrated under reduced pressure. To the resulting residue was added 200 mL of hexane, the mixture was stirred at 50° C. for 1 hour, and then gradually cooled to room temperature with stirring. The resulting light brown solids were filtered, and the solids were washed with hexane to obtain the titled compound (35.0 g, 39.4 mmol, 106% yield). The structure was confirmed by 1H-NMR and LC/MS.
• the present invention relates to a guanidine derivative and others, and thus can be utilized in the fields of chemistry, biochemistry, pharmaceutical and polymer chemistry.

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